Itahashi and Irie et al. used multiple sequencing methods (ATAC, RNAseq, and sc versions) to profile Treg differentiation in the TME of NSCLC tumors. Compared to CD8+ and conventional CD4+ TILs, tumor-infiltrating Tregs displayed a unique open chromatin profile in which BATF was identified as a critical epigenetic and transcriptional regulator of Treg remodeling, differentiation, and activation. Deleting BATF in Tregs in the TME significantly delayed tumor growth in animal models, while high Treg BATF expression was associated with poor relapse-free survival in NSCLC, including PD-1-non-responders, and several other tumor types (lung, kidney and melanoma).
Contributed by Katherine Turner
ABSTRACT: Regulatory T (Treg) cells suppress effective antitumor immunity in tumor-bearing hosts, thereby becoming promising targets in cancer immunotherapy. Despite the importance of Treg cells in tumor immunity, little is known about their differentiation process and epigenetic profiles in the tumor microenvironment (TME). Here, we showed that Treg cells in the TME of human lung cancers harbored a completely different open chromatin profile compared with CD8+ T cells, conventional CD4+ T cells in the TME, and peripheral Treg cells. The integrative sequencing analyses including ATAC, single-cell RNA, and single-cell ATAC sequencing revealed that BATF, IRF4, NF-κB, and NR4A were important transcription factors for Treg cell differentiation in the TME. In particular, BATF was identified as a key regulator, which leveraged Treg cell differentiation through epigenetically controlling activation-associated gene expression, resulting in the robustness of Treg cells in the TME. The single-cell sequencing approaches also revealed that tissue-resident and tumor-infiltrating Treg cells followed a common pathway for differentiation and activation in a BATF-dependent manner heading toward Treg cells with the most differentiated and activated phenotypes in tissues and tumors. BATF deficiency in Treg cells remarkably inhibited tumor growth, and high BATF expression was associated with poor prognosis in lung cancer, kidney cancer, and melanoma. These findings indicate one of the specific chromatin remodeling and differentiation programs of Treg cells in the TME, which can be applied in the development of Treg cell-targeted therapies.
Author Info: (1) Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Tokyo 104-0045/Chiba 277-8577, Japan.
Author Info: (1) Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Tokyo 104-0045/Chiba 277-8577, Japan. (2) Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Tokyo 104-0045/Chiba 277-8577, Japan. (3) Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Tokyo 104-0045/Chiba 277-8577, Japan. Department of Hematology, National Cancer Center Hospital East, Chiba 277-8577, Japan. (4) Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Tokyo 104-0045/Chiba 277-8577, Japan. Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan. (5) Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Tokyo 104-0045/Chiba 277-8577, Japan. (6) Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Tokyo 104-0045/Chiba 277-8577, Japan. Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan. (7) Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Tokyo 104-0045/Chiba 277-8577, Japan. (8) Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan. (9) Department of Thoracic Surgery, National Cancer Center Hospital East, Chiba 277-8577, Japan. (10) Department of Thoracic Surgery, National Cancer Center Hospital East, Chiba 277-8577, Japan. (11) Department of Thoracic Surgery, National Cancer Center Hospital East, Chiba 277-8577, Japan. (12) Department of Hematology, National Cancer Center Hospital East, Chiba 277-8577, Japan. (13) Division of Pathology, National Cancer Center Hospital East, Chiba 277-8577, Japan. (14) Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan. (15) Regulation of Host Defense Team, Division of Microbiology and Immunology, Center for Infectious Disease Education and Research, Osaka University, Osaka 565-0871, Japan. Laboratory of Lymphocyte Differentiation, WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan. (16) Laboratory of Lymphocyte Differentiation, WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan. Division of Microbiology and Immunology, Center for Infectious Disease Education and Research, Osaka University, Osaka 565-0871, Japan. Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences (IMS), Kanagawa 230-0045, Japan. (17) Graduate School of Frontier Sciences, University of Tokyo, Chiba 277-8562, Japan. (18) Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Tokyo 104-0045/Chiba 277-8577, Japan. (19) Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Tokyo 104-0045/Chiba 277-8577, Japan. Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
